Superantigens may play an important role in cancer, acquired immune deficiency syndrome (AIDS), and arthritis, and staphylococcal enterotoxins are prototype superantigens. The objective of this proposal is to determine the structural basis for staphylococcal enterotoxin superantigen activation of lymphocytes. In particular, the P.I. proposes to determine the structural basis for staphylococcal enterotoxin interaction with both major histocompatibility complex (MHC) class II molecules on antigen-presenting cells and T-cell receptors (TCR) on responding T lymphocytes. This will entail determination of the following structures: certain staphylococcal enterotoxin superantigens, superantigen sites which interact with receptors, and receptor sites which are bound by these superantigens. These studies should help identify structural motifs which convey the property of superantigenicity, and provide insights into how to modulate such activity. The P.I. proposes to achieve the objective through the specific aims which follow: (1) Identify the binding site(s) on staphylococcal enterotoxin A (SEA) and toxic shock syndrome toxin-1 (TSST-1) for MHC class II molecules and TCR using peptides, recombinant native and mutant molecules, and their antibodies; (2) Determine the structures of SEA and TSST-1 peptides as well as recombinant native and mutant molecules to facilitate identification of structural motifs which convey the property of superantigenicity for possible identification of other superantigens in a variety of systems; (3) Determine the agonist / antagonist properties of SEA and TSST-1 receptor binding peptides and recombinant mutant molecules for enhancement of these properties through peptide engineering; (4) Identify the site(s) on MHC class II molecules and TCR that bind SEA and TSST-1; (5) Determine the modulating effect of enterotoxin superantigens on autoimmune diseases such as experimental allergic encephalomyelitis (EAE); and (6) Determine the structural basis for the interaction of the minor lymphocyte stimulating (Mls) superantigens with MHC class II molecules and TCR and its possible relationship to staphylococcal enterotoxin binding to receptors.